The principal objective of this proposal is to develop an Aspergillus fumigatus VesiVax(r) vaccine. The studies proposed in this Phase I Application will specifically address refining a liposomal based vaccine using the defined candidate antigens (i.e., Aspf3, Aspf9 and AspfHemolysin) that will provide protective immune responses against aspergillosis. Our central hypothesis is that a highly immunogenic liposome delivery system developed by Molecular Express (VesiVax(r)) can be used to rapidly design and engineer candidate vaccines against A. fumigatus. The liposomal Aspergillus vaccine candidates will be tested in a relevant immunocompromised mouse model for their ability to protect against a pulmonary Aspergillus challenge. Preliminary data using Aspf3, Aspf9 and Aspf Hemolysin are very encouraging. Here, we intend to follow up those studies by determining the minimum number of Aspf proteins needed for the vaccine and the dosage of vaccine that is optimal. We will also determine whether the Aspf vaccine will provide additional protection to animals requiring antifungal therapy. It is conceivable that A. fumigatus may break-through the host immunity in vaccinated patients that are also immunocompromised (e.g., patients on chemotherapy). We will test whether the Aspf vaccination prior to infection can ameliorate the fungal infection when antifungal therapy is used post infection. We will determine the colony forming units in the lungs, bronchial-alveolar lavage (BAL) and kidneys to assess the extent of Aspergillus fungal infection. In addition to survival and signs of disease, we will measure cytokine levels in the BAL and lungs to determine if there is a decrease of inflammatory cytokines in the BAL and lung tissue in infected mice. Histopathological analysis will be done on the lungs to determine the level of fungal infection and the type and extent of the immune response in these tissues. From these studies described in this SBIR Phase I application, the most effective candidate Aspergillus vaccine candidate will be used for advancement to clinical evaluation and development of a commercial product. Commercialization will be done with the intent of using our Aspf vaccine to prevent or ameliorate disease in the primary patient population, the immunocompromised hosts such as those individuals undergoing a solid organ transplant, bone marrow transplant or cancer chemotherapy. In these patients, the opportunity exists to immunize the patient prior to the onset of the most severe immunosuppression, with the goal that the acquired resistance from the vaccine can carry over through the course of the immunosuppression, thus reducing patient mortality and infection with Aspergillus.